1. Field of the Invention
The present invention relates to preventives or remedies for infection, anti-endotoxin agents, vaccine adjuvants and growth promoters for man or animals.
The present invention relates also to foods or feeds to prevent or remedy infection of man or animals.
The present invention relates also to foods or feeds to prevent or remedy human or animal diseases caused by endotoxin.
The present invention relates also to foods or feeds functioning as adjuvants for vaccines for man or animals.
The present invention relates also to foods or feeds promoting human or animal growth.
2. Description of the Prior Art
Recently, various diseases or many infectious diseases of man and animals are believed to be caused by weakened immunological functions or an insufficiency of immunological functions. In man, for example, immunological functions are weakened or made insufficient by bronchial asthma, allergic disease, joint rheumatism, autoimmune disease, nutrition lesion, surgical operations, aging, cancer, transplant of organ, or conception, resulting in concurrence of infectious diseases such as infectious diseases of respiratory organs, septicemia, and infectious diseases of urinary tracts. To treat these diseases and infectious diseases, many kinds of antibiotics are administered. However, when the antibiotic is continuously administered, its efficacy becomes weaker due to development of resistant bacteria which leads to a recently closed-up problem of hospital infection. Therefore, it is desired not to depend only on antibiotics but to develop drugs or food which enforce immunological functions themselves to thereby prevent or treat infection and to decrease dosage of antibiotics.
In the livestock and fishing industries, a large scale raising or overcrowded raising is performed to raise domestic animals, poultry or cultured fish efficiently. Such raising environment causes stresses in the animals and immune insufficiency in the animals' infancy, which leads often to various kinds of infectious diseases. As a countermeasure for this, high dosages of the antibiotics for treating or preventing diseases are administered to the animals. However, such a high dosage necessitates it in return to administer more kinds or other kinds of antibiotics in order to cope with problems of residual antibiotics, increase of resistant bacteria, and diseases caused by resistant bacteria.
Generally, known preventives or remedies comprise a single component or a plurality of components having similar structures as an active ingredient which is (are) prepared by extracting, condensing or synthesizing the components. Consequently, it is apprehended that a long time or high dosage of the preventive or remedy causes side effects.
Substances activating immunity to thereby prevent infection were found, such as some of Bacillus subtilis, Lactobacillus bifidus, and Clostridium. The immunity activating effect or infection preventive effect of the followings were reported: Egg albumen (Japanese Patent Application Laid-Open No. H3-251573), a mixture of two or more selected from egg albumen, bacteria and garlic (National Publication of Translation of PCT Application No. H8-509211), one or more selected from Rosa roxburghii, mugwort and cabbage and a mixture thereof (JPA Laid-Open No. H6-116158), and Glycyrrhiza component (JPA Laid-Open No. H9-143-85).
It is known that one can use bagasse as a culture medium for fungi such as shiitake mushrooms, fomes japonicus, straw mushrooms, hackberris, and mushrooms. Also reported are an anti-virus agent of which active ingredient is an extract from basidiomycetes (JPA Laid-Open No. H2-286623, JPA Laid-Open No. H4-66536) and an anti-virus substance obtained by fractionating and purifying an aqueous extract from cultivated substances obtained by culturing shiitake fungus on a medium comprising bagasse and rice bran (JPA Laid-Open No. H5-4929).
An anti-virus agent is know which comprises active ingredient polysaccharides and cytokinin generated by basidiomysetes cultured on bagasse as a medium (JPA Laid-Open No. S55-157517). However, the same inventor later filed another patent application on an anti-animal virus agent essentially comprising both polysaccharides and water soluble lignin as active ingredients which are prepared by subjecting bagasse to enzyme activity or boiling bagasse, followed by extraction (JPA Laid-Open No. S57-106624). However, data on an agent comprising, as the active ingredients, polysaccharides with a molecular weight of from 10,000 to 50,000 and water soluble lignin with a molecular weight of from 50,000 to 100,000 prepared by subjecting bagasse to the enzyme activity and extracting it are the same as the data described in the aforesaid JPA Laid-Open No. S55-157517. There is not described datum of any anti-virus test on the components extracted by boiling and extracting bagasse. (It should be noted that abstract description about the boiling and extraction was deleted later in an invalidation appeal procedure.) Therefore, the contents of JPA Laid-Open No. S57-106624 are substantially the same as and nothing more than those of JPA Laid-Open No. S55-157517. As summarized above, basidiomycetes containing fungi such as shiitake mushrooms and fomes japonicus are known to be physiologically active and generally used in health food. Some of the extracts from these fungi cultured bagasse are known to have anti-virus effects. To extract them, mycelia of basidiomycetes, fungi, or enzymes produced thereby are necessary.
As already described above, when infectious diseases, especially those caused by bacteria, take place, antibiotics are generally administered. In these cases, especially, where the antibiotics are administered when the causal bacteria have proliferated above a certain level, all the bacteria die at once and endotoxin present in the bacteria moves to a host, which may cause endotoxin shock in the host. Besides this sudden move of the endotoxin in blood caused by the antibiotics, the bacteria or the endotoxin thereof may circulate in blood to cause septicemia or septicemia shock.
To prevent or remedy these diseases caused by endotoxin, some anti-endotoxin agents have been reported: a method of using an antibody as an anti-endotoxin agent to remedy diseases caused by endotoxin(JPA Laid-Open No. S61-500355, National Publication of Translation of PCT Application No. H4-506447, JPA Laid-Open No. H2-104534, JPA Laid-Open No. H2-134329, JPA Laid-Open No. H6-62844, and National Publication of Translation of PCT application No. H6-501931), a method of using hirudine which is a thrombin inhibitor (JPA Laid-Open No. H6-165691), a method of using denatured C reactive protein (National Publication of Translation of PCT Application No. H7-501545), a method of using 1,4-thiazine derivatives (JPA Laid-Open No. S63-301876), a method of using heterocyclic derivatives (JPA Laid-Open No. H3-240779), a method of using an anti-endotoxin agent comprising taurine as an active ingredient (JPA Laid-Open No. H10-158158), a method of using a novel compound (JPA Laid-Open No. H5-194470).
Recently, a vaccine adjuvants attract attention as an additive to vaccine because they are considered to play an important role for enhancing antigenicity of the vaccine. Particularly, the vaccine adjuvant is indispensable for an inactivated vaccine, because expression of the effect of the vaccine is unstable.
Currently, adjuvants clinically used for man and animals are those topically used together with vaccines, for example, plant oils such as sesame oil and colza oil, mineral oils such as complete Freund's adjuvant and incomplete Freund's adjuvant, aluminum hydroxide, and aluminum sulfate.
Studies have been made on vaccine adjuvants. Usually, an adjuvant is mixed with vaccine and is injected or orally administered. Seeking for a safer and natural adjuvant effect, studies have been reported on orally administered adjuvants derived from natural products. As oral adjuvants, reported are an adjuvant for influenza virus vaccine containing Shouseiryutou as an effective ingredient (JPA Laid-Open No. H7-173069), avian oral adjuvant containing effective ingredient NaF (JPA Laid-Open No. H10-59869), and an oral adjuvant containing an effective ingredient mutant enterotoxin (National Publication of Translation of PCT application No. H10-505059) were reported. As adjuvants derived from plants, the following has been reported: a specific lipid emulsion type of adjuvant containing a fatty oil originating from a plant, polysaccharide vaccine adjuvant comprising purified and detoxicated endotoxin and trehalose dimicolate (JPA Laid-Open No. S63-22029), an adjuvant composition containing a synthetic hydrophobic lipopolysaccharide and a surfactant component originating from a plant (JPA Laid-Open No. H5-255117), vaccine containing asemannan extracted from aloe as an adjuvant (National Publication of Translation of PCT application No. H7-506565).
Also, use of detoxicated toxins such as mutated cholera toxin and mutated heat-labile toxin and cytokine IL-12 are studied (Experimental Medicine (Jikken Igaku), 17, 199(1999)).
In the livestock and fishing industries, it is desired to grow domestic animals, fish and shrimps faster for shipping them, or to raise productivity by growing weak domestic animals, fish or shellfish which are usually considered to be too small and too weak to grow to be shipped. Many studies have been made for the purpose of growing animals faster by increasing feed efficiency, of changing taste and flavor of feed to make inexpensive and less-preferred feed more effective, or of growing weak domestic animals, fish and shellfish which are usually considered to be too weak to grow to be shipped.
As a means to increase a weight of a domestic animal, the following has been reported: an additive for animal feed containing soy bean, toad venom, araliaceae, and animal gallbladder (JPA Laid-Open No. H7-313070), a method of using a mixture of beer yeast and ethanol (JPA Laid-Open No. S48-61266), a method of using an antibiotic, multhiomycin (JPA Laid-Open No. S52-54013), a method of using a titanium complex (JPA Laid-Open No. S58-76050), a method of using globulin-containing substance (JPA Laid-Open No. S61-132143), and a method of using a carbazate (JPA Laid-Open No. S61-145156).
As a method for promoting animal growth, the following has been reported: a method of using β-phenethanolamine (JPA Laid-Open No. S59-155343), a method of using an epithelial cell growth factor (JPA Laid-Open No. S62-240625), a method of using a morphorin derivative (JPA Laid-Open No. H1-6262), and a method of using forskolin (JPA Laid-Open No. H1-320956).
As a method for decreasing a feed demanding rate to thereby improve an efficiency of weight increase of domestic animals, the following has been reported: a method of using fruit-origin vinegar (JPA Laid-Open No. S48-103364), a method of using a porcine prolactin (JPA Laid-Open No. H1-230531), and a method of using a product of a bacteriolytic enzyme and protease (JPA Laid-Open No. H2-207756).
As a method of changing preference for animal food to thereby increase a weight, a method of using hexanol or hexanal was reported (JPA Laid-Open No. H7-313067).
As a method of decreasing diseases such as diarrhea to thereby promote growth and weight increase, the following has been reported: a method of using a fructoligosaccharide (JPA Laid-Open No. S60-34134), a method of using an inulo-oligosaccharide (JPA Laid-Open No. S61-40754), a method of using galactosyl disaccharide (JPA Laid-Open No. H4-360652), a method of using a specific polysaccharide having β-1,3-glucan as a main chain (JPA Laid-Open No. H7-50999), an agent for increasing weight and enhancing immunity comprising, as an active ingredient, bacterial cells deprived of capsules (JPA Laid-Open No. H2-11519), and a method for enhancing immunity and increasing weight using a feed containing common-purslane (JPA Laid-Open No. H6-141784).
The preventive or remedial effect, the anti-endotoxin effect, and the vaccine adjuvant effect are all related to immunity. However, their functional mechanism are different from one another, and, accordingly, all of the preventive or remedial agents cannot work as an anti-endotoxin agent or a vaccine adjuvant. The preventive or remedial effect is that against viruses or bacteria causing infectious diseases, and is different from that against endotoxin produced by bacteria. Some having a greater preventive or remedial effect for infection raise an antibody titer of a vaccine, but others may cancel the effect of a vaccine by attacking an attenuated vaccine when they coexist together with the vaccine. The anti-endotoxin effect and the vaccine adjuvant effect are different from each other both in an object to be affected and in functional mechanism. As a consequence, a natural material having all of these effects has not been reported.
Natural preventives or remedies and anti-endotoxin agents previously reported have limited uses, because they must be orally administered in a large amount in order to express effects, or they have so strong taste, smell, or flavor that, when added to food or feed in their effective amounts, they affect taste or smell of food or feed, or raise costs. Therefore, a material is desired which has taste or smell allowable to be added to a wide range of food or feed, express a preventive or remedial effect in a small dosage against infectious diseases, and is inexpensive and of natural product-origin. Most of the natural preventive or remedy agents and anti-endotoxin agents previously reported comprise a specific ingredient as an active ingredient and it is apprehended that a long term or high dosage of them causes side effects. Therefore, among natural materials which show a preventive or remedial effect for infectious diseases in a small dosage, particularly one which comprises a plurality of active ingredients and is more natural, is desired.
Vaccine adjuvants previously reported include chemical compound adjuvants, inorganic adjuvants and biological adjuvants. Those are purified compounds, inorganic materials, or detoxicatedones of enterotoxin or endotoxin produced by bacteria. These conventionally used adjuvants do not steadily express the effects and sometimes cause a side effect of producing IgE. Recently, a natural and safer adjuvant, particularly one expressing the effects via an oral administration, is desired.
Growth promoters previously reported include chemical compounds, plants or extracts therefrom, microorganisms such as yeasts, waste materials such as deoiled soy beans, and biologically active substances contained in enzymes, proteins, or cells. However, there were only a few growth promoters which were inexpensive and easily prepared from a natural source.
An object of the present invention is to provide a preventive or remedy for infection, a preventive or remedy for endotoxin shock (an anti-endotoxin agent), a vaccine adjuvant and a growth promoter, which are safe and effective to man or animals.
Another object of the present invention is to provide a food or an animal feed comprising the preventive or remedy for infection, the anti-endotoxin agent, the vaccine adjuvant or the growth promoter.